Cardiovascular disease is the leading cause of morbidity and mortality in patients with Type 2 diabetes mellitus (Type 2 DM). Despite the knowledge that vascular inflammation is a critical determinant for the development of the accelerated atherosclerosis observed in this population, there is a lack of knowledge about the mechanism(s) responsible for the increased susceptibility to vascular inflammation and atherosclerosis in these patients. Our preliminary data indicates that vitamin D receptor signaling modulates adhesion, migration, and foam cell formation in macrophages and appears to decrease hypertension in humans and atherosclerosis in mice. The objective of our proposal is to delineate the mechanism(s) by which vitamin D modulates the susceptibility to vascular inflammation and atherosclerosis in Type 2 diabetes. We hypothesize that vascular inflammation induced by vitamin D deficiency elevates blood pressure, diminishes arteriovascular flow, and promotes atherosclerosis in diabetes. We will examine this hypothesis through two main lines of investigation. In Aim 1 we will determine whether vitamin D deficiency-induced atherosclerosis depends on activation of stress-related kinase (JNK2), known to affect atherosclerosis in mice, and define whether the mechanism for increased atherosclerosis is vitamin D receptor (VDR) dependent in macrophages. In Aim 2, translating our preliminary observations to humans, we will examine if vitamin D replacement in hypertensive, diabetic patients with vitamin D deficiency decreases blood pressure, improves vascular endothelial function, and promotes an anti-atherogenic phenotype in macrophages. The results of this research may reveal novel insights into the high incidence of cardiovascular disease in patients with Type 2 DM, and suggest a potential new therapeutic target to reduce hypertension and cardiovascular risk in this population. In addition, these findings may offer critical information that will establish the need for widespread screening for vitamin D deficiency or routine supplementation in this high-risk population. Finally, these studies could provide the foundation for future research to evaluate the effects of vitamin D and/or the new vitamin D analogs on common complications affecting diabetic patients, such as cerebrovascular disease, dementia, diabetic nephropathy, and retinopathy. PUBLIC HEALTH RELEVANCE: Effective treatments for cardiovascular disease in patients with diabetes remain one of the largest unmet needs in the public health. This proposal postulates vitamin D as a novel therapeutic agent to decrease vascular inflammation and cardiovascular disease in patients with Type 2 diabetes mellitus. In addition, these findings may offer critical information that will establish the need for widespread screening for vitamin D deficiency or routine supplementation in this high-risk population. Finally, these studies could provide the foundation for future research to evaluate the effects of vitamin D/ vitamin D analogs on common complications affecting diabetic patients, such as cerebrovascular disease, dementia, diabetic nephropathy and retinopathy.